Thyroid hormones are known to be useful in treating conditions associated with impaired thyroid hormone function. Impaired thyroid activity may, for example, occur spontaneously or be the result of surgical removal of the thyroid gland, thyroiditis, or decreased function secondary to pituitary degeneration resulting in hypothyroidism. Conditions secondary to the hypothyroidism include myxedema, cretinism, and obesity.
Thyroid hormones are generally unstable and insufficiently soluble in water for use in many conventional liquid compositions. Consequently, various solid dosage forms (e.g., tablets) have been used for administering such agents. Liquid dosage forms (particularly aqueous solutions), however, are often more convenient to administer (particularly to, for example, companion animals) compared to tablets and other solid dosage forms.
Thyroid hormones include, for example, levothyroxine. Levothyroxine is an iodinated amino acid of the thyroid gland that exerts a stimulating effect on metabolism. Kendall, J. Am. Med. Assoc., 64, p. 2042 (1915). Levothyroxine is also known as L-thyroxine; L-T4; 0-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodotyrosine; and L-3,5,3′,5′-tetraiodothyronine. It is commercially available under various trade names, including Synthroid, Levothroid, Levoxyl, Unithroid, and Soloxine.
When used to treat a thyroid disorder, levothyroxine is often administered in the form of a sodium salt:
Such salts include, for example, levothyroxine sodium pentahydrate (CAS number: 6106-07-06) and levothyroxine sodium hydrate (CAS number: 25416-65-3). Levothyroxine sodium has conventionally been used in tablet form having a unit dose of about 0.1 mg per tablet.
International Patent Application Publication No. WO 95/20955 discusses liquid compositions comprising a thyroid hormone, including levothyroxine sodium. Those compositions reportedly contain from 40% to 96% ethanol (by volume) and from 4% to 50% water (by volume), and have a pH of from 9 to 12.
Various cyclodextrins have been reported to improve the solubility of sparingly-water-soluble compounds. For example, U.S. Pat. No. 6,407,079 discusses pharmaceutical compositions comprising inclusion compounds of sparingly-water-soluble or water-instable drugs with β-cyclodextrin ethers or esters. And U.S. Pat. No. 4,983,586 discusses the use of a composition comprising from 20% to 50% hydroxypropyl-β-cyclodextrin in a method for decreasing precipitation of a lipophilic or water-labile drug near the injection site and/or organs following parenteral administration.
U.S. Pat. No. 5,955,105 discusses levothyroxine compositions comprising a β-cyclodextrin. Those compositions, however, are characterized as being solid compositions, i.e., less than 4.5% (by weight) water.
International Patent Application Publication No. WO 97/19703 discusses oral, parenteral, and transdermal pharmaceutical compositions comprising levothyroxine sodium and an α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. WO 97/19703 reports that γ-cyclodextrin provided the greatest improvement in the aqueous solubility for L-thyroxine sodium of the cylcodextrins tested. WO 97/19703 further reports that 2-hydroxypropylated β-cyclodextrin and maltosyl-β-cyclodextrin were not “feasible solubilizing agents for thyroxine, since they did not significantly improve the aqueous solubility of thyroxine even at higher applied concentrations.”
There continues to be a need for liquid thyroid hormone formulations for oral administration that, for example, enable consistent dosing, are simple to administer, and/or remain stable. The following disclosure describes such formulations, as well as methods for making and using such formulations.